The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

Abstract

Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens. Priming of macrophages with MPLA, CPG oligodeoxynucleotides (CpG ODN), or β-glucan induces a macrophage metabolic phenotype characterized by mitochondrial biogenesis and increased oxidative metabolism in parallel with increased glycolysis, cell size and granularity, augmented phagocytosis, heightened respiratory burst functions, and more effective killing of microbes. The mitochondrion is a bioenergetic organelle that not only contributes to energy supply, biosynthesis, and cellular redox functions but serves as a platform for regulating innate immunological functions such as production of reactive oxygen species (ROS) and regulatory intermediates. This review will define current knowledge of leukocyte metabolic dysfunction during and after sepsis and trauma. We will further discuss therapeutic strategies that target leukocyte mitochondrial function and might have value in preventing or reversing sepsis-and trauma-induced immune dysfunction.

Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID‐19 pneumonia

“…This could lead to an altered immune response with a possible increased susceptibility to secondary infections. Again, the mitochondrial alterations are reminiscent of those observed in sepsis (Japiassu et al, 2011;Arulkumaran et al, 2016;Jang et al, 2019;McBride et al, 2020). Several studies in PBMC from patients with a systemic infection reported significant depolarization of mitochondrial membrane potential, reduced mitochondrial respiration, and severe impairment of mitochondrial electron transport chain complexes I, III, and IV (Japiassu et al, 2011;Jang et al, 2019;McBride et al, 2020).…”

“…Again, the mitochondrial alterations are reminiscent of those observed in sepsis (Japiassu et al, 2011;Arulkumaran et al, 2016;Jang et al, 2019;McBride et al, 2020). Several studies in PBMC from patients with a systemic infection reported significant depolarization of mitochondrial membrane potential, reduced mitochondrial respiration, and severe impairment of mitochondrial electron transport chain complexes I, III, and IV (Japiassu et al, 2011;Jang et al, 2019;McBride et al, 2020). An association between mitochondrial dysfunctions and decreased ATP concentration in skeletal muscles has been correlated with organ failure, thus implying that bioenergetic failure can be a crucial pathological mechanism underlying multiorgan dysfunction (Brealey et al, 2002).…”

Hip Fracture Leads to Transitory Immune Imprint in Older Patients

“…If immune scar observed in HF is similar to the one observed in sepsis, it could be interesting to consider these two common complications in elderly populations as unique models to propose strategies to restore immunity after prolonged stress-induced immune suppression. Most recently, the concept of metabolic dysfunction has emerged as a factor underlying impaired function of the innate and adaptive immune systems of severely injured patients (31).…”

Hypothesis: Mechanisms That Prevent Recovery in Prolonged ICU Patients Also Underlie Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

“…As described in the previous section, cytokines are likely culprits in the central (i.e., hypothalamic and pituitary) suppression of the HPA, HPS and HPT axes in prolonged critical illness ( 29 ). Pro-inflammatory cytokines and inflammation also hinder normal mitochondrial function during critical illness ( 181 ). The alterations in cytokines found in critical illness likely have many further implications that have yet to be fully understood ( 182 ) which is also the case for ME/CFS ( 183 ).…”